DESCRIPTION (adapted from the application): The long-term goal of this research is to develop novel anti-biological threat agents using combinatorial methods. The specific objectives of this program are the development of novel anti-smallpox agents. The main projects involve: preparation of libraries of drug-like molecules by high-throughput, parallel synthesis methods, and combinatorial biosynthesis for testing in high-throughput screens. The targets include vaccinia topoisomerase and H1-phosphatase. This project will utilize the following methods: (1) organic synthesis, both in solution and on the solid phase, and combinatorial chemistry; (2) microbial molecular genetics, combinatorial biosynthesis and natural product fermentation; and (3) viral molecular genetics, heterologous protein expression, in vitro enzyme assays, and antiviral assays in tissue culture.